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ThrombophiliaFor the Clinician

Dr Cleona Duggan

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L > R by 4 cm

L > R by 2.5 cm

24-year-old healthy woman on birth control pills

Case Study

Reprinted with permission from Moll S. Arterioscler Thromb Vasc Biol. 2008;28:373-379.

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XIIVII

X

Clot

Va

Thrombin Antithrombin

act. protein C

Protein S

Natural Anticoagulant System

Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:114-128.

506506 act. protein C

Normal Factor V

Va

Factor V Leiden

506 act. protein C

506

Va

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DiscoveredPrevalence

Caucasians African Americans

Factor V Leiden1

1994 5% 1.2%

Prothrombin 20210 mutation2 1996 2% 0.5%

Factor V Leiden/Prothrombin 20210

1. Ridker PM, et al. JAMA. 1997;277:1305-1307.2. Varga EA, Moll S. Circulation. 2004;110:e15-e18.

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· Prothrombin 20210 = II20210 = G20210A: mutation in promoter region, leading to increased factor II levels

Ho WK, et al. Arch Intern Med. 2006;166:729-736.

Factor V Leiden/Prothrombin 20210

· Moderate/mild risk factor for DVT/PE

· Only very mild risk factor for recurrent VTE (FVL OR, 1.41; prothrombin 20210 OR, 1.72)

· Only marginal risk factor for arterial clots

· Mild risk factor for pregnancy loss

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Prevalence:• 1:500 (C and S) to 1:5,000 (AT)

How do you test?• Activity• >100 mutations account for each

deficiency; thus: genetic testing not done in routine practice

Acquired deficiency:• Liver disease (C, S, AT)• Warfarin therapy (C, S)• Estrogens, pregnancy (S)• Inflammatory diseases (S)• Heparin therapy (AT)• Acute thrombosis (S, AT)

Protein C, S, and Antithrombin Deficiency

Moll S. J Thromb Thrombolysis. 2006;21:7-15.

Practical point:• Always question the diagnosis!

How do you treat?• Consider AT concentrate• Severe neonatal C deficiency:

protein C concentrate

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tPA=tissue plasminogen activator; PAI-1=plasminogen activator inhibitor 1; TAFI=thrombin activatable fibrinolysis inhibitor.

Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:114-128.

Other Thrombophilias

• Elevation of factor VIII

• Elevations of fibrinogen, factors II, IX, XI

• Fibrinolysis abnormalities:– Plasminogen deficiency

– Decreased tPA levels and polymorphisms

– Elevated PAI-1 level and polymorphisms

– Elevated TAFI levels

• Myeloproliferative disorders (JAK-2 mutation)

• Paroxysmal nocturnal hemoglobinuria (PNH)

8Reprinted with permission from Pomp ER, et al. Br J Haematol. 2007;139:289-296.

Obesity and Thrombophilia

Obesity is a risk factor for VTE

Conclusion: lose weight

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Od

ds

rati

o

BMI

<20 ≥20 and <22.5

≥22.5 and <25

≥25 and <27.5

≥27.5 and <30

≥30 and <32.5

≥32.5 and <35

≥35

np 160 416 817 925 704 402 190 220nc 256 865 1236 1102 626 311 154 133

9Pomp ER, et al. Br J Haematol. 2007;139:289-296.

Obesity and Thrombophilia

BMI Risk FactorOR for Venous

Thrombosis 95% CI

OC use

< 25 No 1

≥ 30 No 3.04 1.66-5.57

≥ 30 Yes 23.78 13.35-42.34

Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE

10Pomp ER, et al. Br J Haematol. 2007;139:289-296.

Obesity and Thrombophilia

BMI Risk FactorOR for Venous

Thrombosis 95% CI

OC use

< 25 No 1

≥ 30 No 3.04 1.66-5.57

≥ 30 Yes 23.78 13.35-42.34

Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE

FVL

< 25 No 1

≥ 30 No 2.48 2.13-2.88

≥ 30 Yes 7.86 4.70-13.15

11Pomp ER, et al. Br J Haematol. 2007;139:289-296.

Obesity and Thrombophilia

BMI Risk FactorOR for Venous

Thrombosis 95% CI

OC use

< 25 No 1

≥ 30 No 3.04 1.66-5.57

≥ 30 Yes 23.78 13.35-42.34

Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE

FVL

< 25 No 1

≥ 30 No 2.48 2.13-2.88

≥ 30 Yes 7.86 4.70-13.15

Prothrombin 20210

< 25 No 1

≥ 30 No 2.45 2.12-2.82

≥ 30 Yes 6.58 2.31-18.69

12Pomp ER, et al. Am J Hematol. 2008;83:97-102.

Smoking and Thrombophilia

Smoking Risk FactorOR for Venous

Thrombosis 95% CI

Factor V Leiden

No No 1

Current No 1.43 1.26-1.63

Current Yes 5.05 3.46-7.38

Combined effect of smoking and genetic risk factors for VTE

– Conclusion: stop smoking

Prothrombin 20210

No No 1

Current No 1.41 1.25-1.60

Current Yes 6.06 2.67-13.76

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Contraceptives and Thrombosis1,2

Risk compared to women who do not

take OCP

Absolute risk/year

All women of reproductive age 1 1 : 12,500

OCP 2-6x ’d 1 : 3,000

Hetero FVL 4x ’d 1 : 3,000

Hetero FVL + OCP 20-30x ’d 1 : 500

BMI >30 + OCP 24x ’d 1 : 500

Homozygous FVL + OCP 50-100x ’d 1 : 150

BMI >30 + smoking + OCP ??? ???

Homozygous FVL + BMI >30 + smoking + OCP

??? ???

OCP=oral contraceptive; BMI=body mass index.

1. Varga E. J Genet Couns. 2007;16:261-277.2. Pomp ER, et al. Br J Haematol. 2007;139:289-296.

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Thrombophilia Testing

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Pros1. “Power to prevent clots”

– surgery (red flag)

– birth control pill, pregnancy

2. Explanations

3. Influence on medical treatment– choice of drug (antiplatelet vs

anticoagulation)

– length of warfarin therapy

– intensity of warfarin therapy

Pros and Cons of Thrombophilia Testing

Cons1. Cost

2. Worry

3. Bad medical advice

4. Insurance implications

Moll S. J Thromb Thrombolysis. 2006;21:7-15.

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Any patient with

spontaneous VTE

Younger patient with VTE +

family history

Any patient

with VTE

General population

Younger patient

with VTE

Arch-conservativeUltra-liberal

Nobody

Who Should Be Tested?1-4

1. Grody WW, et al. Genet Med. 2001;3:139-148.2. Walker ID, et al. Br J Haematol. 2001;114:512-528.3. Nicolaides AN, et al. Int Angiol. 2005;24:1-26.4. Van Cott EM, et al. Arch Pathol Lab Med. 2002;126:1281-1295.5. Baglin T, et al. Br J Haematol. 2010;149:209-220.

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Am Coll Med Geneticists, 20014 Br Committee for

Standards in Haematol, 20105

Europ Genetics Foundation, Mediterranean League on Thromboembolism, Internat. Union of Angiology, etc, 20051

Which Patient to Test for Thrombophilia?

CAP, 20022

1. Nicolaides AN, et al. Int Angiol. 2005;24:1-26.2. Van Cott EM, et al. Arch Pathol Lab Med. 2002;126:1281-1295.3. The Thrombosis Interest Group of Canada. Available at:

http://www.tigc.org/eguidelines/hypercoagstates.htm. 4. Grody WW, et al. Genet Med. 2001;3:139-148.5. Baglin T, et al. Br J Haematol. 2010;149:209-220.

Arch-conservativeUltra-liberal

Thrombosis Interest Group of Canada, 20063

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· VTE occurring at a younger age (ie, <50 years)· Unprovoked VTE· Recurrent VTE

When to Consider Thrombophilia Testing

Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:114-128.

· Thrombosis at an unusual site (splanchnic, sinus/cerebral, or renal veins)· Unusually extensive spontaneous VTE· Family history of VTE· Asymptomatic individual with family history of strong thrombophilia

– Antithrombin deficiency– Protein C deficiency– Protein S deficiency– Homozygous factor V Leiden– Homozygous prothrombin mutation– Compound thrombophilias

· Recurrent VTE while adequately anticoagulated· Unexplained arterial thromboembolism in a young person (ie, no

arteriosclerosis risk factors, no cardio-embolic source)· ≥3 unexplained pregnancy losses before week 10, or ≥1 loss after week 10

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Family Implications of Thrombophilia

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1. To put the person on anticoagulants

2. To manage the individual differently:· Lifestyle changes (obesity, smoking)

· Advice on oral contraceptives, hormone therapy

· Airline travel

· Pregnancy

· Surgery

Why to Test an Asymptomatic Family Member

Moll S. J Thromb Thrombolysis. 2006;21:7-15.

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Key Points About Positive Family History

1. Noboa S, et al. Thromb Res. 2008;122:624-629.2. Bezemer ID, et al. Arch Intern Med. 2009;169:610-615.

· Positive family history (1st degree relative) is VTE risk factor (2.5-4.2 fold increased risk)2

· Risk is independent of presence of known genetic thrombophilias

· Risk is due to unknown risk factor

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Strategy for Familial Testing

Proband’s thrombophilia

Male Family Member

Sons Brothers

Hetero FVL or hetero prothrombin 20210 no no

Homo FVL or homo prothrombin 20210 no reasonable

Double hetero reasonable reasonable

C, S, AT reasonable reasonable

“Reasonable,” because: consider LMWH with airline travel, cast, non-major surgery; prolonged after major surgeries.

“Yes,” because: advise against oral contraceptives/hormone therapy; give ante- and postpartum anticoagulation.

Slide courtesy of Moll S.

Female Family Member

Daughters Sisters

no no

no yes

yes yes

yes yes

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Lifestyle Changes

1. Lose weight

2. Stop smoking

3. Know the symptoms of DVT and PE

4. Know the risk factors for DVT and PE

5. Know your family history